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Predicting the Role of IL-10 in the Regulation of the Adaptive Immune Responses in Mycobacterium avium Subsp. paratuberculosis Infections Using Mathematical Models.

Magombedze G, Eda S, Stabel J - PLoS ONE (2015)

Bottom Line: The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type).We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011).In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, 37996-1527, United States of America.

ABSTRACT
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular bacterial pathogen that causes Johne's disease (JD) in cattle and other animals. The hallmark of MAP infection in the early stages is a strong protective cell-mediated immune response (Th1-type), characterized by antigen-specific γ-interferon (IFN-γ). The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type). Interleukin-10 (IL-10) is believed to play a critical role in the regulation of host immune responses to MAP infection and potentially orchestrate the reversal of Th1/Th2 immune dominance during disease progression. However, how its role correlates with MAP infection remains to be completely deciphered. We developed mathematical models to explain probable mechanisms for IL-10 involvement in MAP infection. We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011). Our models predicted that IL-10 can have different roles during MAP infection, (i) it can suppress the Th1 expression, (ii) can enhance Th2 (IL-4) expression, and (iii) can suppress the Th1 expression in synergy with IL-4. In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP. We also predicted that Th1-mediated responses (IFN-γ) can lead to high expression of IL-10 and that infection burden regulates Th2 suppression by the Th1 response. Our models highlight areas where more experimental data is required to refine our model assumptions, and further test and investigate the role of IL-10 in MAP infection.

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Effect of IL10—Th2 (IL4) synergy inhibition on Th1 cells.Simulation showing increased suppression of Th1 cells when there is IL-10—Th2 (IL4) synergy. Suppression of the Th1 response accompanied by loss of protection, increased disease progression and CFU shedding. Simulation of IL-10—Th2 (IL4) synergy were generated by a model with the assumption that IL-10 and IL-4 (Th2) interact synergistically to inhibit the expression of the Th1 responses. IL-10—Th2 (IL-4) synergy was modelled using the term, , with a1 = 0.005 while the rest of the model parameters are kept at their baseline values given in Table 2. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL10, green-Th2 cells, pink-infected macrophages. The yellow shading represents the effect of IL-10 inhibition only, while the violet colour represents the effects of IL10 and IL4 synergy.
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pone.0141539.g005: Effect of IL10—Th2 (IL4) synergy inhibition on Th1 cells.Simulation showing increased suppression of Th1 cells when there is IL-10—Th2 (IL4) synergy. Suppression of the Th1 response accompanied by loss of protection, increased disease progression and CFU shedding. Simulation of IL-10—Th2 (IL4) synergy were generated by a model with the assumption that IL-10 and IL-4 (Th2) interact synergistically to inhibit the expression of the Th1 responses. IL-10—Th2 (IL-4) synergy was modelled using the term, , with a1 = 0.005 while the rest of the model parameters are kept at their baseline values given in Table 2. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL10, green-Th2 cells, pink-infected macrophages. The yellow shading represents the effect of IL-10 inhibition only, while the violet colour represents the effects of IL10 and IL4 synergy.

Mentions: To investigate the effect of IL-10-Th2 (IL4) synergy in MAP infection, we assumed two different roles for IL-10. First, we assumed that IL-10 can suppress Th1 expansion while at the same time the expressed Th2 (IL-4) will suppress Th1 expression (see the supplementary information and Table 5 on how IL-10—Th2 (IL4) synergy was modelled). Using this assumption, we observed increased cell populations (shown in Fig 5) except for the population of Th1 cells. These simulations show the difference in Th1 suppression achieved when only IL-10 inhibition is assumed (no synergy) and when there is IL-10—Th2 (IL4) synergy. Apart from showing increased MAP infection, simulations also predict increased bacterial shedding associated with IL-10—Th2 (IL4) synergy. Also, Fig 5 show that as the level of the expressed Th1 cells decline, IL-10 expression also declines, however, this declining effect is only translated/transferred to a slow steady increase in the population of infected macrophages and free bacteria. Once Th1 expression is depleted, the population of infected macrophages and free bacteria will increase even when the Th2 (which is not protective) expression is increased. Increased population of infected macrophages will lead to increased CFU shedding, while free bacteria will skew Th0 cell differention towards Th2, hence a dominant Th2 response. Once Th1 expression is low, infected macrophages will accumulate. This will not help differention selection to favour Th1 expansion because of the IL-10—Th2 (IL4) synergy. Second, we assumed that IL-10 enhances Th2 cell proliferation (IL-4 expression) while the Th2 response inhibits Th1 differentiation. S2 Fig shows that this assumption will achieve qualitatively simular results to the results of the first assumption. However, the mechanism through which these results are achieved are different. In this case, IL-10 does not directly inhibit Th1 cells, but does so through enhancing Th2 expression, which in turn suppresses the Th1 response.


Predicting the Role of IL-10 in the Regulation of the Adaptive Immune Responses in Mycobacterium avium Subsp. paratuberculosis Infections Using Mathematical Models.

Magombedze G, Eda S, Stabel J - PLoS ONE (2015)

Effect of IL10—Th2 (IL4) synergy inhibition on Th1 cells.Simulation showing increased suppression of Th1 cells when there is IL-10—Th2 (IL4) synergy. Suppression of the Th1 response accompanied by loss of protection, increased disease progression and CFU shedding. Simulation of IL-10—Th2 (IL4) synergy were generated by a model with the assumption that IL-10 and IL-4 (Th2) interact synergistically to inhibit the expression of the Th1 responses. IL-10—Th2 (IL-4) synergy was modelled using the term, , with a1 = 0.005 while the rest of the model parameters are kept at their baseline values given in Table 2. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL10, green-Th2 cells, pink-infected macrophages. The yellow shading represents the effect of IL-10 inhibition only, while the violet colour represents the effects of IL10 and IL4 synergy.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664406&req=5

pone.0141539.g005: Effect of IL10—Th2 (IL4) synergy inhibition on Th1 cells.Simulation showing increased suppression of Th1 cells when there is IL-10—Th2 (IL4) synergy. Suppression of the Th1 response accompanied by loss of protection, increased disease progression and CFU shedding. Simulation of IL-10—Th2 (IL4) synergy were generated by a model with the assumption that IL-10 and IL-4 (Th2) interact synergistically to inhibit the expression of the Th1 responses. IL-10—Th2 (IL-4) synergy was modelled using the term, , with a1 = 0.005 while the rest of the model parameters are kept at their baseline values given in Table 2. The shading of cell populations before IL-10 inhibition are represented by the colours: grey-CFUs, blue-Th1 cells, red-bacteria, cyan-IL10, green-Th2 cells, pink-infected macrophages. The yellow shading represents the effect of IL-10 inhibition only, while the violet colour represents the effects of IL10 and IL4 synergy.
Mentions: To investigate the effect of IL-10-Th2 (IL4) synergy in MAP infection, we assumed two different roles for IL-10. First, we assumed that IL-10 can suppress Th1 expansion while at the same time the expressed Th2 (IL-4) will suppress Th1 expression (see the supplementary information and Table 5 on how IL-10—Th2 (IL4) synergy was modelled). Using this assumption, we observed increased cell populations (shown in Fig 5) except for the population of Th1 cells. These simulations show the difference in Th1 suppression achieved when only IL-10 inhibition is assumed (no synergy) and when there is IL-10—Th2 (IL4) synergy. Apart from showing increased MAP infection, simulations also predict increased bacterial shedding associated with IL-10—Th2 (IL4) synergy. Also, Fig 5 show that as the level of the expressed Th1 cells decline, IL-10 expression also declines, however, this declining effect is only translated/transferred to a slow steady increase in the population of infected macrophages and free bacteria. Once Th1 expression is depleted, the population of infected macrophages and free bacteria will increase even when the Th2 (which is not protective) expression is increased. Increased population of infected macrophages will lead to increased CFU shedding, while free bacteria will skew Th0 cell differention towards Th2, hence a dominant Th2 response. Once Th1 expression is low, infected macrophages will accumulate. This will not help differention selection to favour Th1 expansion because of the IL-10—Th2 (IL4) synergy. Second, we assumed that IL-10 enhances Th2 cell proliferation (IL-4 expression) while the Th2 response inhibits Th1 differentiation. S2 Fig shows that this assumption will achieve qualitatively simular results to the results of the first assumption. However, the mechanism through which these results are achieved are different. In this case, IL-10 does not directly inhibit Th1 cells, but does so through enhancing Th2 expression, which in turn suppresses the Th1 response.

Bottom Line: The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type).We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011).In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, 37996-1527, United States of America.

ABSTRACT
Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular bacterial pathogen that causes Johne's disease (JD) in cattle and other animals. The hallmark of MAP infection in the early stages is a strong protective cell-mediated immune response (Th1-type), characterized by antigen-specific γ-interferon (IFN-γ). The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type). Interleukin-10 (IL-10) is believed to play a critical role in the regulation of host immune responses to MAP infection and potentially orchestrate the reversal of Th1/Th2 immune dominance during disease progression. However, how its role correlates with MAP infection remains to be completely deciphered. We developed mathematical models to explain probable mechanisms for IL-10 involvement in MAP infection. We tested our models with IL-4, IL-10, IFN-γ, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011). Our models predicted that IL-10 can have different roles during MAP infection, (i) it can suppress the Th1 expression, (ii) can enhance Th2 (IL-4) expression, and (iii) can suppress the Th1 expression in synergy with IL-4. In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP. We also predicted that Th1-mediated responses (IFN-γ) can lead to high expression of IL-10 and that infection burden regulates Th2 suppression by the Th1 response. Our models highlight areas where more experimental data is required to refine our model assumptions, and further test and investigate the role of IL-10 in MAP infection.

Show MeSH
Related in: MedlinePlus